Submissions for variant NM_007294.4(BRCA1):c.1297del (p.Ala433fs)

dbSNP: rs80357794

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111585	SCV000299574	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111585	SCV000325007	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579657	SCV000682946	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-04	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with ovarian cancer (PMID: 21324516). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496361	SCV000698844	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1297delG (p.Ala433Profs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1326T>A, p.Cys442X; c.1360_1361delAG, p.Ser454fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121238 control chromosomes. The variant has been reported in affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496361	SCV001582009	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54190). This variant is also known as 1416delG. This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 21324516). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala433Profs*8) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Ambry Genetics	RCV000579657	SCV002692895	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The c.1297delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1297, causing a translational frameshift with a predicted alternate stop codon (p.A433Pfs*8). This deletion has been reported in one Italian ovarian cancer patient not selected for family history (Zhang S et al. Gynecol. Oncol. 2011 May; 121(2):353-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000111585	SCV004215039	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-04	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111585	SCV000144053	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496361	SCV000587120	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353811	SCV000591322	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Ala433ProfsX8 variant was identified in the literature in at least 2 of 113994 proband chromosomes (frequency: 0.00002) from individuals or families with breast or ovarian cancer (Judkins 2005, Zhang 2011). The variant was also identified in dbSNP (ID: rs80357794) “With pathogenic allele”, the GeneInsight COGR database (classified as pathogenic by a clinical laboratory), and in the Clinvar database with submissions from BIC (classified as pathogenic) and Invitae (classification not provided). The p.Ala433ProfsX8 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 433 and leads to a premature stop codon at position 440. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.